1. ¹CNRS FRE 2445, Université de Versailles/St Quentin, 45, avenue des Etats-Unis, Versailles 78035, France
2. ²CNRS UMR 8125, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif 94805, France
3. ³Institut National de la Recherche Agronomique, UR 121, Laboratoire de Recherches de Technologie Laitière, 35042 Rennes Cedex, France

Correspondence: C Brenner, E-mail: cbrenner@genetique.uvsq.fr

Received 13 April 2004; Revised 14 June 2004; Accepted 18 June 2004; Published online 20 September 2004.

Abstract

The mitochondrial permeability transition pore complex (PTPC) is involved in the control of the mitochondrial membrane permeabilization during apoptosis, necrosis and autophagy. Indeed, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), two major components of PTPC, are the targets of a variety of proapoptotic inducers. Using co-immunoprecipitation and proteomic analysis, we identified some of the interacting partners of ANT in several normal tissues and human cancer cell lines. During chemotherapy-induced apoptosis, some of these interactions were constant (e.g. ANT-VDAC), whereas others changed strongly concomitantly with the dissipation of the mitochondrial transmembrane potential and until nuclear degradation occurred (e.g. Bax, Bcl-2, subunits of the respiratory chain, a subunit of the phosphatase PP2A, phospholipase PLC 4 and IP3 receptor). In addition, a glutathione-S-transferase (GST) interacts with ANT in normal tissue, in colon carcinoma cells and in vitro. This interaction is lost during apoptosis induction, suggesting that GST behaves as an endogenous repressor of PTPC and ANT pore opening. Thus, ANT is connected to mitochondrial proteins as well as to proteins from other organelles such as the endoplasmic reticulum forming a dynamic polyprotein complex. Changes within this ANT interactome coordinate the lethal response of cells to apoptosis induction.